Abstract

The impact of having left-handers (LHs) among one's close relatives, called familial sinistrality (FS), on neuroanatomical markers of left-hemisphere language specialization was studied in 274 normal adults, including 199 men and 75 women, among whom 77 men and 27 women were positive for FS. Measurements of the surface of a phonological cortical area, the “planum temporale” (PT), and gray and white matter hemispheric volumes and asymmetries were made using brain magnetic resonance images. The size of the left PT of subjects with left-handed close relatives (FS+) was reduced by 10%, decreasing with the number of left-handed relatives, and lowest when the subject's mother was left-handed. Such findings had no counterparts in the right hemisphere, and the subject's handedness and sex were found to have no significant effect or interaction with FS on the left PT size. The FS+ subjects also exhibited increased gray matter volume, reduced hemispheric gray matter leftward asymmetry, and, in LHs, reduced strength of hand preference. These results add to the increasing body of evidence suggesting multiple and somewhat independent mechanisms for the inheritance of hand and language lateralization.

Introduction

The overwhelming prevalence of both right-handedness and left hemisphere specialization for language is arguably the most salient feature of human brain organization. Whether these 2 characteristics coincide by chance or are under the control of common genetic and/or epigenetic factors remains a much debated issue. Shortly after his discovery that a lesion in the left hemisphere of a right-handed patient can lead to aphasia (Broca 1861), Paul Broca conjectured that symmetric findings should be expected in left-handed subjects. This claim was based on the fact that handedness has strong behavioral asymmetry in humans, a phenomenon that Broca linked to left hemisphere dominance for language. Since then, handedness has been taken as a measure of brain hemisphere specialization under the hypothesis that both language and manual laterality are genetically determined to be hosted by the left hemisphere. Aphasiology studies have confirmed the strong relationship between right-handedness and left hemisphere dominance for language, but a different concept has emerged from the work of Hécaen on a large sample of left-handed patients bearing brain lesions. Hécaen showed that the lateralization of language and visuospatial functions were weaker in left-handers (LHs) and named this feature “ambilaterality” (Hécaen and Sauguet 1971; Hardyck and Petrinovich 1977).

The search for relationships between anatomical asymmetries in the brain, hemispheric specialization of language, and handedness was revolutionized in 1968 when Geschwind and Levitsky (1968) reported on the leftward asymmetry of a temporal cortex area involved in speech sound processing, namely, the “planum temporale” (PT). This seminal finding, which was obtained through measurements of the PT surface area in postmortem brains, was considered as proof of an anatomical substrate for left hemisphere dominance for language. Later ex vivo studies (Teszner et al. 1972) confirmed leftward asymmetry of the PT in the general population and showed that it was possibly related to differences in the orientation of the Sylvian fissure in the left and right hemisphere (reviewed by (Witelson 1977). Cytoarchitectonic studies have further refined our knowledge by showing that the asymmetric PT cortex corresponds to area Tpt, which hosts the unimodal associative auditory cortex (Galaburda et al. 1978).

PT area measurements were not performed in healthy subjects using modern neuroimaging techniques until the 1980s (Steinmetz et al. 1989). Right-handers (RHs) were confirmed to have large leftward PT asymmetry (for a review, see (Shapleske et al. 1999) related to global brain torsion, named the brain torque (Barrick et al. 2005). Because of the reduced occurrence of left hemisphere dominance for language in LHs (Satz 1979; Hécaen et al. 1981), Steinmetz et al. (1991) investigated differences in PT asymmetry with respect to handedness and reported lower PT asymmetry in LHs, a finding confirmed by some but not all (Habib et al. 1991; Foundas et al. 1995).

It was not before the 1990s that functional imaging helped establishing the functional role of PT in language processing, first confirming its involvement in the processing of tones and language sounds (Binder et al. 1996, 2000). It was further demonstrated that PT was more involved in word than in tone processing, this involvement being leftward asymmetric (Jancke et al. 2001; Jancke, Wustenberg, Schulze, and Heinze 2002) and was more specifically recruited by rapidly changing cues, allowing the phonetic analysis of language sounds (Jancke, Wustenberg, Scheich, and Heinze 2002). Functional imaging has also been used for direct testing Geschwind and Levitsky conjecture, namely, the proposal that PT anatomical asymmetry and language lateralization are linked. We have shown that the left PT surface area positively correlates with increases in left temporal cortex blood flow during speech processing (Tzourio et al. 1998; Josse et al. 2006). Others did not find such relationship between PT asymmetry and functional asymmetries (measured with functional magnetic resonance imaging) that were triggered by a semantic decision task (Eckert et al. 2006). The discrepancy between the findings of the 2 studies is only apparent because it has been shown that when a language task calls more for frontal than for temporal lobe processing, the relationship between the left PT size and the task-related functional asymmetry is looser, handedness becoming the best predictor of the interindividual variability of functional lateralization for the task. Actually, subjects’ handedness explains most of the variability in Broca's area activation during language production (Josse et al. 2006), in line with study of Knecht et al. (2000) using functional transcranial Doppler sonography showing that right handedness relates to a lower incidence of rightward brain asymmetries during language production. On the opposite, handedness has a lower impact on functional language comprehension asymmetries, interindividual variability during story listening being explained by a combination of handedness, left PT surface area, and brain volume (Josse et al. 2006). These observations are part of accumulating evidence suggesting that graded language skills/comprehension may correlate with planar size while the neural substrate of the qualitative (left or right) laterality appears related to a more general left hemisphere role in motor execution (Schluter et al. 2001).

Actually, the potential impact of handedness on language lateralization and related brain asymmetries may go beyond the effect of the subject handedness itself. Specifically, familial sinistrality (FS), namely, the presence of one or more LHs among one's close relatives has long been postulated to modulate brain lateralization for language. Such effects of FS were first uncovered by Hécaen who observed that subjects with a history of FS exhibited fewer language deficits after left hemisphere brain lesions. This finding led him and others to postulate the existence of additive effects of handedness and FS on brain lateralization. According to this theory, RHs without left-handed relatives (FS−) should be the most strongly lateralized subjects for language functions, whereas LHs with left-handed relatives (FS+) should be the most ambilateral ones (Hécaen and Sauguet 1971; Hardyck and Petrinovich 1977; Hécaen et al. 1981). Hécaen's observations suggest that handedness in a family may have correlates that go beyond a simple change in hand preference, possibly being translated as reduced left hemisphere specialization in some family members, whether they were right- or left-handed.

Considering that having a LH among close relatives is a trait shared by more than 30% of human subjects (Spiegler and Yeni-Komshian 1983), it is surprising that the effects of FS on the anatomical substrates of language lateralization have been so far largely overlooked. As a matter of fact, the literature on FS and PT asymmetry is limited to the study by Steinmetz et al. (1991) cited above reporting a reduction of PT asymmetry in FS+ left-handed subjects and the literature on FS and functional areas to one functional imaging studies reporting a reduced leftward language dominance in FS+ and FS− left-handed subjects during a word classification task (Hund-Georgiadis et al. 2002). Accordingly, not taking into account the impact of FS may be one of the reasons why the literature on the relationship between PT asymmetry and handedness has been so disparate; some authors reporting no relationship (Moffat et al. 1998; Sequeira et al. 2006), whereas others found significant ones (see Steinmetz et al. 1991; Habib et al. 1991; Foundas et al. 1995).

The primary goal of the present study was thus that the presence of FS would reduce the left PT surface area and/or PT asymmetry, thereby attempting to bring support to Hécaen's conjecture of a reduced lateralization in FS+ subjects. We also tested whether or not such an effect would purely add on that of the subject's handedness described in the literature by some authors. To conduct this investigation, we measured the PT surface areas of 274 young healthy volunteers, including 104 subjects with left-handed relatives and 170 with none. Also, among these 274 subjects, 80 were left-handed and 194 right-handed. Such a sample size was thought necessary because another reason that can explain the disparate literature on PT and handedness is the relative small sample sizes of many published studies. A secondary goal of our study was to assess whether FS would act on the global organization of brain's lateralization and not solely at the level of the PT. For this, the hemispheric gray and white matter tissue volumes and their asymmetries were measured in the same subjects.

Methods

Subjects

The sample for the present study was constituted first by gathering several samples of subjects who had participated in various cognitive neuroimaging experiments in our laboratory during the period 2002–2006 and second by recruiting additional left-handed subjects in order to obtain a sufficient number of LHs. All subjects were recruited through the same protocol, and all were naive with the goals of the study. In particular, FS was not a selection criterion. All subjects gave their written informed consent to the experiment they were recruited for, each experiment having been approved by our local ethic committee.

Handedness and FS Distribution in the Study Sample

The sample was composed of 274 subjects (199 males and 75 females), including 194 RHs (134 males, 60 females) and 80 LHs (65 males and 15 females). Handedness was self-reported by the subjects (Table 1). The occurrence of self-reported left-handedness in this sample was higher in men (33%) than women (20%, P = 0.035, χ2 test) due to a larger recruitment of left-handed male volunteers.

Table 1

Number of subjects, manual preference, and manual skill according to sex, self-reported handedness, and FS

 Manual preference Manual skill
 
 Right hand Left hand 
All (274)    
    F (75)    
        RH (60)    
            FS− (38) 85 ± 16 50 ± 4 43 ± 5 
            FS+ (22) 96 ± 7 50 ± 7 43 ± 6 
        LH (15)    
            FS− (10) −84 ± 24 48 ± 6 50 ± 5 
            FS+ (5) −69 ± 17 48 ± 3 49 ± 2 
    M (199)    
        RH (134)    
            FS− (90) 86 ± 16 57 ± 6 50 ± 6 
            FS+ (44) 83 ± 22 56 ± 5 50 ± 5 
        LH (65)    
            FS− (32) −75 ± 29 51 ± 6 54 ± 6 
            FS+ (33) −62 ± 32 54 ± 6 55 ± 7 
 Manual preference Manual skill
 
 Right hand Left hand 
All (274)    
    F (75)    
        RH (60)    
            FS− (38) 85 ± 16 50 ± 4 43 ± 5 
            FS+ (22) 96 ± 7 50 ± 7 43 ± 6 
        LH (15)    
            FS− (10) −84 ± 24 48 ± 6 50 ± 5 
            FS+ (5) −69 ± 17 48 ± 3 49 ± 2 
    M (199)    
        RH (134)    
            FS− (90) 86 ± 16 57 ± 6 50 ± 6 
            FS+ (44) 83 ± 22 56 ± 5 50 ± 5 
        LH (65)    
            FS− (32) −75 ± 29 51 ± 6 54 ± 6 
            FS+ (33) −62 ± 32 54 ± 6 55 ± 7 

Note: Manual preference was assessed with the EI, manual skill with the FTT. Values are mean ± SD. F, female; M, male.

The mean age of the sample was 24.3 years (standard deviation [SD] = 6.1 years, range = 18–53). An analysis of variance (ANOVA) revealed that LHs were significantly younger, by 2 years, than RHs (P = 0.015) with no other significant effect due to sex or FS. The average education level of the subjects, measured as the number of school years starting from primary school, was 14.7 years (SD = 2.2 years, range = 9–20) with no significant effect of sex or FS but a small significant difference in favor of RHs (0.8 year, P = 0.030, ANOVA).

FS was self-reported by the subjects. Positive FS (FS+) was defined as the presence of at least one LH among the parents and siblings of a subject. There were 170 subjects (62%) with no left-handed first-degree relatives (FS−), whereas 104 (38%) had at least one. The occurrence of FS was independent of sex (0.36 for females vs. 0.38 for males, P = 0.41), handedness (0.34 for RH vs. 0.47 for LH, P = 0.38), and sex by handedness (P = 0.19). These findings are consistent with previous reports on the occurrence of FS being either similar between right- and LHs (Spiegler and Yeni-Komshian 1983) or slightly more frequent in LHs (Orsini et al. 1985).

The FS+ subjects’ left-handed relative were his/her mother (36.9%), father (19.4%), or sibling (43.7%). No more than one subject had both parents who were left-handed. These proportions are consistent with values derived by others from a large population study (Spiegler and Yeni-Komshian 1983). No effect of sex (P = 0.28) or handedness (P = 0.17) was found on the distribution of this FS pattern. However, among subjects who had one left-handed parent, the proportion of subjects with left-handed mothers was higher for men than women (73% vs. 38%, P = 0.029).

FS was quantified using the adjusted FS proportion (aFS) (Corey and Foundas 2005), a variable that measures the strength of FS with respect to family size. In the subsample of 104 FS+ subjects, the average aFS was 0.22 (SD = 0.088), independent of sex or handedness.

Subject's Manual Preference and Manual Skill

Strength of manual preference was evaluated by the Edinburgh Inventory (EI) score (Oldfield 1971) and further transformed into an ordinal variable based on the EI score absolute value: Subjects with an EI score absolute value equal to 100 were classified as “strong,” those with an EI score absolute value between 60 and 99 as “moderate,” and those below 60 as “weak.” This classification of manual preference strength in 3 categories was under the hypothesis that it was the strength of manual lateralization rather than handedness that may be the relevant variable to investigate an impact of FS. This hypothesis comes form a report conducted by Crow et al. (1998) on cognitive abilities showing, among 12 770 children, that those with the lowest strength of manual lateralization, close to equal hand skill, had the lowest verbal abilities. Crow called this phenomenon the “hemispheric indecision point” and related such low verbal abilities to low hemispheric lateralization of language functions. This result was further confirmed in the BBS internet study showing that subjects using either hand for writing had the lowest scores in the mental rotation test and suffered more frequently from dyslexia (Peters et al. 2006). Manual skill was assessed by the Finger Tapping Test (FTT) (Peters and Durding 1978), which was recorded for both the right and left hand.

Image Acquisition and Analysis

Anatomical images were acquired for each subject on the same 1.5-T MR scanner (General Electric SIGNA Helix, Milwaukee, WI) using a 3D T1-weighted spoiled gradient recall sequence and a 0.9357 × 0.9357 × 1.5 mm voxel size.

Volumetric Measurements

The T1 images were spatially normalized by the SPM5 software assigning individual magnetic resonance images to specific cerebral tissue templates built from the T1 images of 104 subjects included in the sample of the present study (52 men and 52 women, all RHs). All spatial normalization parameters were set to their SPM5 default values. Spatially normalized images were segmented into gray matter, white matter, and cerebrospinal fluid compartments. We then applied a modulation step to each individual's tissue maps to preserve the subject's original tissue quantity after it was transferred to the reference space. Gray matter, white matter, and cerebrospinal fluid volumes were estimated as the integral of voxel intensities over the corresponding modulated tissue partition images, and the total intracranial volume was defined as their sum. A manually traced cerebellar mask was used to exclude this structure from the whole-brain gray and white matter volumes in order to obtain hemispheric gray and white matter values and calculate asymmetry indices by subtracting right hemisphere tissue volumes from their left hemisphere counterparts.

Delineation of PT

The PT surfaces in the left and right hemispheres were delineated on a single brain slice using the knife-cut method (Kulynych et al. 1993). This method simulates the physical removal of the frontal and occipital lobes by a knife cut and has been shown to have an acceptable reproducibility (Shapleske et al. 1999). The fact that Steinmetz et al. (1990) showed that PT cortex folding does not differ between hemispheres makes it the method of choice for PT delineation in a large number of subjects. In the present study, a single expert performed all the tracings so as to remove any variability due to multiple operators. However, the measurement of PT surface variability was expected to remain high due to the large anatomical interindividual differences and anatomical complexity of this area (Habib et al. 1995). After a rigid reorientation of the brain image volume in the stereotactic space, an oblique slice of interest passing through the Sylvian fissure and perpendicular to the midpart of the coronal projection of the PT was reconstructed for each hemisphere using homemade software (Diallo et al. 1998). The orientation of this slice was defined by 2 landmarks, namely, the posterior border of the Heschl's gyrus and the turning point of the Sylvian fissure (Fig. 1). Similar to others (Moffat et al. 1998), the orientation of the slice used for PT delineation was defined separately for each hemisphere because the orientations of the left and right Sylvian fissures are not consistently identical. On this slice, the PT contour was manually outlined using the simultaneous display of 4 incidences: axial, sagittal, coronal, and the plane passing through the Sylvian fissure (Fig. 1). The anterior limit of the PT was indicated by the posterior border of Heschl's gyrus, which corresponds to Heschl's sulcus. As proposed by others, whenever a second Heschl's sulcus or intermediary sulcus (also termed Becq's sulcus) was long and deep enough to individualize a second gyrus, it was included within the PT (Penhune et al. 1996; Knaus et al. 2006). We confounded complete duplication and common stem duplication of Heschl because anatomical landmarks allowing for the definition of a duplication of Heschl's gyrus are not clear-cut and depend on the distance from the midline (Leonard et al. 1998). Note that cytoarchitectonic studies are not helpful on this point because they show that the spatial relationships between micro- and macroscopic landmarks in auditory cortices are loose (Morosan et al. 2001). Laterally, when the transverse posterior gyrus did not traverse the entire superior temporal gyrus, it was extended laterally following the direction of the sulcus. The posterior limit of the PT corresponded to the vertical ascending terminal segment of the Sylvian fissure that is usually easy to identify because of its location posterior to the postcentral sulcus and a typical configuration on the lateral surface with the presence of a small descending branch. When there was no descending branch, the turning point was defined as the point where the superior surface of the Sylvian fissure curved. When no terminal ascending segment was present, the PT included the whole surface of the Sylvian fissure, a configuration occurring in the left hemisphere of 8% of cases and in the right hemisphere of 4% (Ono et al. 1990). Note that neither the descending nor ascending rami, corresponding to the planum parietale, were included.

Figure 1.

Example of manual delineation of the right and left PT. In this subject, the angle of the slice passing through Heschl's gyrus and the ending of the Sylvian fissure was the same and is visible in the left panel of (A) showing the axis of the reconstructed slice allowing the depiction of the PT surfaces on a sagittal slice. On the right, the region of interest defining the left PT is provided, and (B) shows the right PT region of interest.

Figure 1.

Example of manual delineation of the right and left PT. In this subject, the angle of the slice passing through Heschl's gyrus and the ending of the Sylvian fissure was the same and is visible in the left panel of (A) showing the axis of the reconstructed slice allowing the depiction of the PT surfaces on a sagittal slice. On the right, the region of interest defining the left PT is provided, and (B) shows the right PT region of interest.

Statistical Analysis

Characterizing the Relationships between FS, Manual Preference, Manual Skill, and Brain Size in the Study Sample

Before proceeding to the testing of the main hypothesis of the study, we documented the relationships between FS and handedness on manual preference strength, manual skill (FTT score), and brain size. Sex, age, and cultural level were included as covariates in the analysis.

An analysis of covariance (ANCOVA) model was used for the FTT scores and brain volume, whereas a logisitic regression model was used for the manual preference strength (ordinal variable).

Testing the Effects of FS and Handedness on PT Surface Areas and Asymmetry

FS and handedness and their interaction were entered as the main factors of an ANOVA of PT measurements. We used a repeated-measures design in order to include both the left and right PT measures in the same ANOVA, the corresponding within-subject “side” effect standing for the amplitude of PT asymmetry.

Apart from FS and handedness, sex and global brain volume were also entered as confounding factors in the model explaining PT variability.

Sex was included because women may recover better from aphasia, suggesting that they could be less lateralized (Hécaen et al. 1981; Bryden et al. 1983). However, the existence of sex differences in brain lateralization is still under question (Wallentin 2009), and reduced PT asymmetry in women has not been consistently reported (Kulynych et al. 1994; Watkins et al. 2001; Knaus et al. 2004). Actually, the large difference between the brain volumes of men and women may explain most of the sex differences in brain anatomy (Luders et al. 2002; Leonard et al. 2008; Sommer et al. 2008).

Brain volume was included because it is a key factor acting on brain lateralization by increasing interhemispheric transfer times increase, thereby constraining the clustering of speech processes within one hemisphere in large brains (Ringo et al. 1994). Indeed, we previously reported that brain volume interacts with handedness and left PT surface on the interindividual variability in the functional lateralization for language comprehension and production (Josse et al. 2006). Finally, age and cultural level were also taken into account.

In order to study the relationship between aFS and PT surfaces, an ANCOVA including aFS as a covariate was conducted on the PT values of the FS+ subjects.

Testing the Effects of FS and Handedness on Brain Tissue Volumes and Asymmetries

Effects of FS and handedness on hemispheric gray matter and white matter volumes were assessed using a model identical to that used for PT.

Results

Characterizing the Relationships between FS, Manual Preference, Manual Skill, and Brain Size in the Study Sample

Manual Preference

Values of the Edinburgh score are given in Table 1. The analysis of manual preference strength values revealed significant main effects of sex (P < 0.040) and handedness (P < 0.004), as well as significant interaction effects of sex by FS (P < 0.026) and handedness by FS (P < 0.012).

The sex and sex-by-FS interaction effects were due to the fact that, in FS+ subjects, women had a stronger hand preference than men, with a larger proportion of “strong” and a smaller proportion of “weak” (FS+ women: 63% strong vs. 4% weak; FS+ men: 25% strong vs. 31% weak; Fig. 2).

Figure 2.

Manual preference strength distribution in the subjects as a function of their sex, FS, and their manual preference strength. Note that FS+ women were more strongly lateralized than men and that left-handed FS+ males showed the highest proportion of “weak” strength of manual preference. W: weak preference, EI absolute value ≥0 and ≤60; M: moderate preference, Edinburgh score >60 and <100; S: strong preference, Edinburgh score = 100.

Figure 2.

Manual preference strength distribution in the subjects as a function of their sex, FS, and their manual preference strength. Note that FS+ women were more strongly lateralized than men and that left-handed FS+ males showed the highest proportion of “weak” strength of manual preference. W: weak preference, EI absolute value ≥0 and ≤60; M: moderate preference, Edinburgh score >60 and <100; S: strong preference, Edinburgh score = 100.

The effects of handedness and the handedness-by-FS interaction were due to the fact that, in LH, there was a larger proportion of “weak” and smaller proportion of “strong” in FS+ than FS− subjects (LH—FS+: 21% strong, 42% weak; FS−: 42% strong, 21% weak; see Fig. 2).

Manual Skill

The FTT scores are provided in Table 1. The ANCOVA revealed that FS had neither significant main effect (P = 0.34) nor interaction with either sex (P = 0.84) or handedness (P = 0.23) on FTT scores. A sex (P < 0.0001) main effect together with an hemisphere-by-handedness interaction (P < 0.0001) were observed: Men were found to be more skilled than women and all subjects more skilled with their self-reported preferred hand. In addition, we found that the difference in manual skill between the preferred hand and nonpreferred hand was larger in RH than LH because of a poor performance of RH with their left hand (P < 0.0001, ANOVA). FTT scores were found to decrease with age (P = 0.018).

Brain Size

The FS had no significant effect (P = 0.44) or interaction with sex (P = 0.32) or handedness (P = 0.35) on whole-brain volume. Sex was found to have the expected significant effect (P < 0.0001), men having a larger average brain volume than women. There was a significant sex-by-handedness interaction (P = 0.034): left-handed women had a smaller brain volume compared with right-handed women, whereas the opposite was found for men (see Table 2). There was a trend of brain volume reduction with age (P = 0.069), but there was no significant effect of cultural level (P = 0.75).

Table 2

Brain, cerebral gray and white matter volumes, and their hemispheric volume asymmetries (left minus right), according to sex, self-reported handedness, and FS

 Brain volume Cerebral gray matter
 
Cerebral white matter
 
 Volume Asymmetry Volume Asymmetry 
     
    RH      
        FS− 1327 ± 110 585 ± 54 1.10 ± 2.8 393 ± 41 −0.05 ± 2.0 
        FS+ 1356 ± 97 599 ± 53 −0.10 ± 2.3 414 ± 40 0.10 ± 2.7 
    LH      
        FS− 1271 ± 114 573 ± 75 0.34 ± 3.3 386 ± 42 −0.61 ± 1.7 
        FS+ 1335 ± 124 613 ± 90 −1.87 ± 3.2 392 ± 36 −1.33 ± 0.93 
     
    RH      
        FS− 1482 ± 102 650 ± 53 1.21 ± 3.0 449 ± 43 0.21 ± 2.4 
        FS+ 1501 ± 123 661 ± 62 0.77 ± 3.4 452 ± 49 0.55 ± 2.7 
    LH      
        FS− 1531 ± 138 672 ± 57 0.07 ± 2.6 463 ± 48 −0.53 ± 2.1 
        FS+ 1504 ± 115 673 ± 67 −0.32 ± 3.3 461 ± 39 −1.00 ± 2.2 
 Brain volume Cerebral gray matter
 
Cerebral white matter
 
 Volume Asymmetry Volume Asymmetry 
     
    RH      
        FS− 1327 ± 110 585 ± 54 1.10 ± 2.8 393 ± 41 −0.05 ± 2.0 
        FS+ 1356 ± 97 599 ± 53 −0.10 ± 2.3 414 ± 40 0.10 ± 2.7 
    LH      
        FS− 1271 ± 114 573 ± 75 0.34 ± 3.3 386 ± 42 −0.61 ± 1.7 
        FS+ 1335 ± 124 613 ± 90 −1.87 ± 3.2 392 ± 36 −1.33 ± 0.93 
     
    RH      
        FS− 1482 ± 102 650 ± 53 1.21 ± 3.0 449 ± 43 0.21 ± 2.4 
        FS+ 1501 ± 123 661 ± 62 0.77 ± 3.4 452 ± 49 0.55 ± 2.7 
    LH      
        FS− 1531 ± 138 672 ± 57 0.07 ± 2.6 463 ± 48 −0.53 ± 2.1 
        FS+ 1504 ± 115 673 ± 67 −0.32 ± 3.3 461 ± 39 −1.00 ± 2.2 

Note: Values are mean ± SD in cubic centimeter. F, female; M, male.

Effects of FS and Handedness on PT Surface Area

Significant effects of FS (P = 0.035) and FS-by-hemisphere interaction (P = 0.015) were found on PT size; FS− subjects had larger left PT surface area than FS+ subjects (677.8 vs. 624.9 mm2, see Table 3), but such an effect did not exist for the right PT surface (476.4 mm2 vs. 477.6 mm2). As a consequence, FS− subjects exhibited significantly more leftward PT asymmetry than FS+ subjects (P = 0.015). There was no significant effect of sex (P = 0.72) or handedness (P = 0.88) and no significant factor interaction on PT surface values. The total intracranial volume was positively correlated with PT surfaces (P=0.015), but there was no correlation with age (P = 0.69) or cultural level (P = 0.74).

Table 3

PT surface area (in millimeters squared) according to sex, self-reported handedness, and FS

 PT surface area
 
 Left Right 
  
    RH   
        FS− 631 ± 150 468 ± 153 
        FS+ 552 ± 158 420 ± 132 
    LH   
        FS− 691 ± 134 411 ± 178 
        FS+ 563 ± 128 478 ± 186 
  
    RH   
        FS− 682 ± 208 478 ± 185 
        FS+ 673 ± 164 503 ± 208 
    LH   
        FS− 718 ± 209 502 ± 201 
        FS+ 619 ± 168 482 ± 196 
 PT surface area
 
 Left Right 
  
    RH   
        FS− 631 ± 150 468 ± 153 
        FS+ 552 ± 158 420 ± 132 
    LH   
        FS− 691 ± 134 411 ± 178 
        FS+ 563 ± 128 478 ± 186 
  
    RH   
        FS− 682 ± 208 478 ± 185 
        FS+ 673 ± 164 503 ± 208 
    LH   
        FS− 718 ± 209 502 ± 201 
        FS+ 619 ± 168 482 ± 196 

Note: Values are mean ± SD. F, female; M, male.

In the subgroup of FS+ subjects (N = 104), an ANCOVA including the aFS showed a negative correlation between left PT size (P = 0.041, see Fig. 4) with no effect of sex and handedness. No such relation was observed for the right PT (P = 0.58).

The FS pattern was found to have a significant effect on the left PT surface (P = 0.014, see Fig. 4); FS− subjects had the largest PT surface (682 mm2, P = 0.0045), whereas FS+ subjects with a left-handed mother had the smallest left PT surface (558 mm2, P = 0.048). This result did not depend on sex, handedness, age, brain volume, or cultural level.

Effects of FS and Handedness on Gray Matter Volume and Hemispheric Asymmetry

FS was found to have significant effects on the brain volume–adjusted cerebral gray matter volume (Table 2, P = 0.024). The FS+ subjects had more gray matter than FS− subjects, which was true for both hemispheres. We also found a hemisphere effect (larger left volume, P = 0.005) and a hemisphere-by-FS interaction; FS− subjects were leftward asymmetrical (left − right hemisphere = 0.91 cm3, P < 0.0001), whereas FS+ subjects exhibited no asymmetry (left − right hemisphere = 0.11 cm3, P = 0.71).

Handedness had no effect on gray matter (P = 0.44), but we noticed a trend for a hemisphere-by-handedness interaction (P = 0.065); RHs were leftward asymmetrical (left − right hemisphere = 0.94 cm3, P < 0.0001), whereas LHs were not asymmetrical (left − right hemisphere = −0.17 cm3, P = 0.59).

No significant interaction was present between FS and handedness (P = 0.22) that combined in an additive way; a larger leftward gray matter asymmetry was present in FS− RH and a rightward asymmetry in FS+ LH (Fig. 2).

Sex had no main effect (P = 0.64) or interaction with FS (P = 0.74).

Gray matter volume increased with brain volume (P < 0.0001) and decreased with age (P < 0.0001), and a significant hemisphere-by-brain volume interaction was present; the left minus right difference in hemispheric gray matter volumes was positively correlated with brain volume (P = 0.017). Cultural level had no effect on gray matter volume (P = 0.19).

Effects of FS and Handedness on White Matter Volume and Hemispheric Asymmetry

As opposed to gray matter, FS had no effect (P = 0.24) on white matter volume (Fig. 3). Also, there was no interaction of FS with sex (P = 0.37), handedness (P = 0.71), or hemisphere (P = 0.53). Rather, we found a significant hemisphere effect (P = 0.010) and hemisphere-by-handedness interaction (P = 0.018) on white matter volume; LHs were significantly rightward asymmetrical (left − right hemisphere = −0.78 cm3, P = 0.0009; Fig. 3), whereas RHs were not significantly asymmetrical (left − right hemisphere = 0.22 cm3, P = 0.20). White matter volume and its left minus right hemisphere difference were both positively correlated with brain volume (P < 0.0001 and P = 0.020, respectively). There was a significant decrease in white matter volume with age (P = 0.017) but no effect of sex (P = 0.81) or cultural level (P = 0.57).

Figure 3.

Gray and white matter volume hemispheric asymmetries (left–right) in subjects depending on the presence of a LH in their family and their handedness. Left: effect of handedness on gray and whiter matter hemispheric asymmetries (RH). Note the hemispheric gray matter leftward asymmetry in RH and the hemispheric white matter rightward in LH. Center: effect of FS on gray and whiter matter hemispheric asymmetries (FS−, FS+). Note the reduced hemispheric gray matter leftward asymmetry in FS+ subjects. Right: interaction between these factors. Note the purely additive effects of FS and handedness hemispheric gray matter asymmetry.*Significant effects at a 0.05 threshold.

Figure 3.

Gray and white matter volume hemispheric asymmetries (left–right) in subjects depending on the presence of a LH in their family and their handedness. Left: effect of handedness on gray and whiter matter hemispheric asymmetries (RH). Note the hemispheric gray matter leftward asymmetry in RH and the hemispheric white matter rightward in LH. Center: effect of FS on gray and whiter matter hemispheric asymmetries (FS−, FS+). Note the reduced hemispheric gray matter leftward asymmetry in FS+ subjects. Right: interaction between these factors. Note the purely additive effects of FS and handedness hemispheric gray matter asymmetry.*Significant effects at a 0.05 threshold.

Figure 4.

Impact of FS on the left PT surface area. Left: note that subjects with a left-handed mother have the lowest left PT surface when compared with either FS− subjects or with a left-handed father or sibling (FS+); right: linear regression analysis of the left PT surface area as a function of the proportion of LHs adjusted for family size.

Figure 4.

Impact of FS on the left PT surface area. Left: note that subjects with a left-handed mother have the lowest left PT surface when compared with either FS− subjects or with a left-handed father or sibling (FS+); right: linear regression analysis of the left PT surface area as a function of the proportion of LHs adjusted for family size.

Discussion

The present study, based on a large sample of individuals, demonstrates that FS has significant effects on brain asymmetries: In our sample of subjects, those who had LHs among close relatives had a smaller left PT surface and reduced PT asymmetry, a larger amount of gray matter but no leftward gray matter hemispheric asymmetry. These concurrent findings can be considered to be the result of the reduced development of leftward asymmetry in these subjects. On the other hand, handedness appears to have an impact on gray and white matter hemispheric asymmetries but not on the PT surfaces. Overall, our results may be taken as supporting Hécaen's hypothesis of additive effects of FS and subject handedness on brain lateralization. Sex has no impact on these findings once brain volume was included as a covariate, a finding consistent with that of others (Leonard et al. 2008). As regards brain volume, its effects were as predicted by Ringo et al. (1994): the larger the subject's brain, the larger its gray and white matter asymmetries.

FS Acts Differently than Handedness on Brain Anatomical Global Organization

The larger amount of gray matter observed in FS+ subjects suggests that the decrease in gray matter density that occurs during the postadolescent period (Sowell et al. 2001) was less pronounced in these subjects. This putative reduced synaptic pruning was particularly marked in the right hemisphere, leading to an absence of leftward asymmetry in the gray matter hemispheric volumes of FS+ subjects compared with FS− subjects.

Another argument favoring the hypothesis of reduced pruning during development in FS+ subjects is that the change in the hemispheric asymmetry of gray matter volume was not accompanied by a concurrent change in white matter volume. This is different from what was observed for the effects of handedness on the same neuroanatomical variables. LHs did exhibit an absence of leftward asymmetry in the gray matter volume, but it was not associated with larger gray matter volumes as observed for FS+ subjects. Rather, LH also presented a significant rightward asymmetry of their hemispheric white matter volume, which was not found in FS+ subjects. The fact that both white and gray matter hemispheric asymmetries were different between RH and LH may be in part related to differences in their motor system control (Herve et al. 2005, 2006). Actually, motor system asymmetry as measured with the FTT was significantly different in RH and LH, and the rightward white matter hemispheric asymmetry is in line with right hemisphere control of the dominant left hand of LH. Alternatively, FS+ and FS− subjects did not differ in their manual ability, nor did they differ in the asymmetry of white matter hemispheric volumes.

It is noteworthy that the effects of FS and handedness on gray matter asymmetries appear to combine in an additive way, as shown by the observation of the largest leftward asymmetry in FS− RH, similar to reduced leftward asymmetries in FS+ RH and FS− LH and to a rightward asymmetry in FS+ LH (Fig. 4). As they stand, these findings on gray matter hemispheric asymmetry are supporting one of conjectures of Hécaen et al. (1981) regarding the effects of FS and handedness interactions.

Although FS did not relate to hand skill asymmetries, a result already highlighted by McKeever (McKeever et al. 2000), it interacted with handedness on the strength of manual preference. The FS− RH exhibited the strongest hand preference. Left-handed FS+ subjects showed lower strength of manual preference. One might have expected that a left-handed subject surrounded by other LH would exhibit stronger left-hand preference (Hardyck and Petrinovich 1977), but our data indicate that this is apparently not the case and that the effect of FS on manual preference is not related to greater exposure to the observation of the manual activity of close left-handed relatives in everyday life. The observation that left-handed FS+ subjects have a weaker preference for their left hand is an additional argument for reduced hemispheric specialization in FS+ subjects, independent of their motor control asymmetry (no difference in FTT asymmetry was observed). In addition, this suggests that populations of men with weak hand lateralization, close to the “hemispheric indecision point” defined by Crow et al. (1998), are very likely to include FS+ subjects. Further studies are clearly needed to evaluate if FS+ has an effect on cognitive abilities in relation with a lower brain lateralization.

As a whole, the differences between FS+ and FS− subjects in gray matter asymmetries and the strength of their manual preference support Hécaen's model of a lesser leftward anatomical lateralization in FS+ left-handed subjects than in FS− right-handed subjects.

FS Is Associated with a Lower PT Surface in the Left Hemisphere, Independent of Sex and Handedness

Our FS+ subjects, regardless of sex and handedness, had a lower left PT surface compared with FS− subjects. Notably, the decrease in left PT surface went in the direction opposite to the overall hemisphere gray matter increase in FS+ subjects (see above). Because no such difference was found for the right PT, FS+ subjects also had reduced PT asymmetry. To the best of our knowledge, there is only one previous report on the impact of FS on PT surface asymmetry (Steinmetz et al. 1991), which had findings somewhat different from ours. In that study, an FS+-related reduction of PT asymmetry was indeed observed, but this finding held for LH only. In the same study, handedness was also reported to impact PT surface asymmetry, with LH showing smaller PT asymmetry than RH, although this result was significant only when the subjects were classified as right- or left-handed according to their finger tapping asymmetry but not when their classification was from their self-report or a hand dominance test.

Nevertheless, our investigation showed no effect of handedness on the PT surfaces, which also appears to be contradictory with other published literature. Actually, as mentioned in the Introduction, the studies that specifically investigated the impact of handedness on PT anatomy included small samples of subjects (Steinmetz et al. 1991; Foundas et al. 1995; Habib et al. 1995). Note, in addition, that no difference in the asymmetry of PT lengths has been evidenced between LH and RH defined by their writing hand by Foundas et al. (2002) in a second study. When classifying the subjects upon the strength of their handedness (consistent or inconsistent), rather than using their preferred hand, this author observed a lesser leftward PT asymmetry in consistent LH than in consistent RH (note that this comparison included only 9 of the 19 LH subjects (Foundas et al. 2002). An absence of difference between LHs and RHs was also reported by Moffat et al. (1998) in a sample of 43 subjects where PT measures were available, including 9 LHs. Note that they showed that leftward asymmetry of the PT was present in male subjects having left hemisphere speech representation measured by fused dichotic listening word test, independent of handedness. More recently, an investigation of 104 healthy subjects classifying consistent LHs (54) and RHs (50) upon their EI scores and taking speech lateralization measured with dichotic-listening and cerebral volume into account did not find any handedness effect on PT asymmetry. Rather, this latter study reported a relationship between language lateralization and PT asymmetry in the group of right-handed males, a finding similar to the report of Moffat et al. (1998) (Sequeira et al. 2006). Our results, which are in agreement with the latter findings as regards the lack of effect of handedness on PT size, also offer a potential explanation of the literature disparate findings on this topic: Besides potential spurious results due to the small sample sizes of many of these studies, all of them but those of Steinmetz et al. (1991) disregarded FS as a possible source of variance of PT size.

Concerning sex, the study conducted by Moffat et al. (1998) did not observe a global effect of sex on PT asymmetry when taking into account brain volume, what is in agreement with the conclusions of 2 meta-analyses (Shapleske et al. 1999; Sommer et al. 2008). In the present study also, the absence of a sex effect with the coexisting presence of a significant brain volume effect clearly indicates that differences between the PT surfaces of men and women can be explained simply by a global brain size effect. Note, however, that our subject sample included only 5 FS+ left-handed women, which may have prevented us from detecting subtle interactions between sex and handedness or sex and FS, though such interactions have been observed in behavioral studies (Casey et al. 1992, 1997; Halpern 1996; D'Andrea and Spiers 2005). Further investigations with a larger sample of FS+ left-handed women are needed to clarify the existence of an impact of gender on the PT surface in interaction with FS and/or handedness, taking account the role of brain volume.

To summarize, we are led to the conclusion that having an LH in one's family might reduce the size of the left PT and, therefore, the PT leftward asymmetry independent of one's handedness. This finding raises the issue of the existence of genetic factors associated with FS that would interplay with the setting up of left hemisphere dominance for language at the level of the left temporal lobe auditory areas although having no influence on the lateralization of manual skill. So far, single-gene models designed to explain the genetic component of handedness heritability are also assumed to explain the heritability of hemispheric language lateralization (McManus and Bryden 1991; Annett 1998; Klar 1999; Crow 2002; Francks et al. 2002, 2003; Van Agtmael et al. 2002; Jones and Martin 2006; Francks et al. 2007; Corballis 2008). Our findings challenge this assumption and call for somewhat different mechanisms for the heritability of handedness and hemisphere language dominance, in agreement both with a previous report of the familial aggregation of language lateralization, which was found to be independent of handedness (Anneken et al. 2004). The detailed identification of such different mechanisms is out of reach today as the search for the genetic determinants of cortical asymmetry has only started recently (Sun et al. 2005). However, a recent genome-wide analysis of human cortical patterning (Abrahams et al. 2007) indicates that some genes may be specifically involved in the shaping of the posterior temporal cortex related to language, regional differential expression of groups of genes being possibly a basic mechanism of cortical networks development (Johnson et al. 2009). With that respect, our observation that FS+ subjects having a left-handed mother exhibited the lowest PT surface area, indicates that some of these genes could be linked to the X chromosome, in agreement with others (Crow 2009; for a review see Corballis 2009).

The fact that FS reduces the size of the left, but not the right, PT surface specialized in the temporal processing of language sounds (Zatorre et al. 1992; Boemio et al. 2005) and is involved in the auditory processing that supports phonological skills (Jäncke and Steinmetz 1993; Shah et al. 2000; Jäncke et al. 2001; Griffiths and Warren 2002) raises the issue of a potential effect of FS on phonological skills. Recent studies have shown that the volume of the left Heschl's gyrus correlates with the extent of cortex activated by auditory stimuli with varying rates (Warrier et al. 2009) and that individuals with a larger left Heschl's gyrus have larger abilities in pitch learning (Wong et al. 2008). The latter findings demonstrate the predictive value of quantitative anatomy in regard to functional and behavioral interindividual variability. Actually, a decrease in the size of the left PT or its asymmetry has been reported in dyslexia (Rumsey et al. 1986; Larsen et al. 1990; Jerningan et al. 1991; Kushch et al. 1993; Filipek 1995; Rumsey et al. 1997; Morgan and Hynd 1998; Habib 2000; Heiervang et al. 2000; Leonard et al. 2001). In addition, Leonard has recently shown that particular anatomical configurations of Heschl and the PT anatomy are found in phonological dyslexic subjects (Leonard et al. 2001, 2006). Within this frame, additional experiments investigating the relationships between FS, the left PT surface, phonological skills, and functional cortex are needed and could be of value to understanding developmental language disorders.

Larger Brain Volumes Have Increased Gray Matter Hemispheric Asymmetry, Independently of Other Factors

Our results demonstrate that brain volume modulates gray and white matter hemispheric asymmetries, with larger leftward asymmetries being associated with larger brains. This observation supports Ringo's hypothesis of a relationship between brain volume and the lateralization of brain function: the larger the brains, the larger the intrahemispheric clustering and hence the larger hemispheric asymmetries (Ringo et al. 1994). In a previous study, we reported an interaction between brain volume, left PT surface, and handedness on the lateralization of language comprehension networks (Josse et al. 2006). The present study allows us to go one step further by demonstrating that, together with brain volume, the subject's FS, rather than handedness, is a determinant of the left PT surface. Further investigations are needed to quantify the impact of a familial history of sinistrality on language networks during speech comprehension in the line of the study of Hund-Georgiadis (2001) who evidenced lower language lateralization in FS+ than FS− LH during word classification task.

Conclusion

FS, a trait shared by more than 30% of humans, appears to have an impact on brain anatomy that is both different and independent from that of handedness. The presence of FS is associated with a reduction of the strength of hand preference, leftward asymmetry of hemispheric gray matter, and development of left PT phonological temporal areas. Notably, FS has no influence on hand motor asymmetry. The role of this factor in the development of hemispheric specialization for language, first studied by Hécaen and Sauguet (1971), may have been hidden by the salience of the handedness phenotype. The present results suggest that the importance of FS in the investigation of speech hemispheric specialization and its disorders should be reconsidered.

The authors wish to thank 2 anonymous reviewers for their in-depth analysis of the present work that triggered a most interesting exchange.

Conflict of Interest: None declared.

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